Emerging Strategies for the Management of Intestinal Failure Kelly Tappenden, PhD, RD, FASPEN Human Nutrition Endowed Professor University Distinguished Teacher-Scholar Provost Fellow University of Illinois at Urbana-Champaign \ Editor-in-Chief, Journal of Parenteral and Enteral Nutrition
Short Bowel Syndrome Underlying disease Surgical restriction or bypass Short bowel Malabsorption
SBS: A Complex and Life-Threatening Disorder A debilitating, complex disorder that may be life-threatening 1,2 Associated with either loss of portions of the intestine or loss of intestinal function 2,3 Typically follows extensive surgical resection of the intestine due to disease, trauma, or congenital defects 2,4 Results in the inability to maintain fluid and nutrient balances through a normal diet 2 Possible causes of resection 3,5 : Vascular catastrophes Complications of bariatric surgery Trauma Malignancy Radiation enteritis Volvulus Strangulated hernias Short bowel fistulas Crohn s disease 1. Hofstetter S, et al. Curr Med Res Opin. 2013;29(5):495-504; 2. O Keefe SJ, et al. Clin Gastroenterol Hepatol. 2006;4(1):6-10; 3. Nightingale JMD. Intestinal Failure. 2001:177-198; 4. Buchman AL. Nutrition. 1997;13(10):907-913; 5. Parrish CR. Practical Gastroenterology. 2005;31:67-106.
SBS Patients Often Require Parenteral Nutrition After resection, absorptive capacity increases through intestinal adaptation 1,2 Before adequate adaptation is achieved, required nutrients and water must be supplied intravenously 2,3 parenteral nutrition (PN) and/or IV fluids In some patients, adaptation is insufficient to overcome the functional length of bowel that was lost, resulting in permanent PN dependency 3,4 1. Sundaram A, et al. J Clin Gastroenterol. 2002;34(3):207-220; 2. Buchman AL, et al. Gastroenterology. 2003;124(4):1111-1134; 3. Misiakos EP, et al. J Clin Gastroenterol. 2007;41(1):5-18; 4. O Keefe SJ, et al. Clin Gastroenterol Hepatol. 2006;4(1):6-10.
Complications of SBS Malabsorption in SBS may lead to complications by causing malnutrition, dehydration, and micronutrient deficiencies 1,2 Many complications of SBS are PS-related. They can be serious and sometimes life-threatening 3 The most relevant malabsorption-related complications The most relevant of SBSPS- related 2,4 complications : of include SBSDiarrhea include 5 : Extreme weight and muscle mass loss Catheter infections Metabolic bone disease Apathy/Depression Hepatic and biliary Reduced disorders wound healing Appearance Reduced quality of of premature life aging Diminished overall health 1. Misiakos EP, et al. J Clin Gastroenterol. 2007;41(1):5-18; 2. Hofstetter S, et al. Curr Med Res Opin. 2013;29(5):495-504; 3. Buchman AL. Dig Dis Sci. 2001;46(1):1-18; 4. Nightingale JMD. Intestinal Failure. 2001:177-198; 5. Buchman AL, et al. Gastroenterology. 2003;124(4):1111-1134.
Ultimate Treatment Goals 1-5 Reduce Malabsorption- Related Symptoms Enhance Absorption Enable Oral/Enteral Nutrition PS prevents 1,4 : Malnutrition Treatments that Dehydration enhance absorptive Adjunctive capacity may medications reduce 1,4 : improve disease management 1,2 Diarrhea Bacterial overgrowth Reduce or Eliminate PS Minimize PS-Related Complications Improved Disease Management 1. Hofstetter S, et al. Curr Med Res Opin. 2013;29(5):495-504; 2. Jeppesen PB, et al. Gut. 2011;60(7):902-914; 3. Parrish CR. Practical Gastroenterology. 2005;31:67-106; 4. Sundaram A, et al. J Clin Gastroenterol. 2002;34(3):207-220; 5. Vipperla K, et al. Expert Rev Gastroenterol Hepatol. 2011;5(6):665-678.
Disease Management: Promoting Intestinal Adaptation SBS diet trophic factors Growth hormone (GH), epidermal growth factor, insulinlike growth factors, keratinocyte growth factor, cholecystokinin, gastrin, insulin, and neurotensin Prebiotic/probiotic therapy Glucagon-like peptide-2 (GLP-2)
Presence of colon-in-continuity enhances probability of enteral autonomy and survival PN dependency probability (%) Survival probability (%) Messing et al. Gastroenterology 1999;117:1043-1050.
Energy absorption increased by functional colon and carbohydrate diet % energy absorbed cho fat Diet cho fat Diet Nordgaard et al., Lancet 1994;343:373-376
Colon important in the digestion of carbohydrates and hence in the salvage of calories in patients with SBS Nordgaard et al., Lancet 1994;343:373-376
Short Chain Fatty Acids Products of carbohydrate and protein fermentation Acetate, propionate, butyrate comprise 83% of SCFAs Enhance structural and functional adaptation in adult rodent small intestine Unanswered questions: 1. Do SCFA enhance intestinal adaptation in the neonatal intestine? 2. Are the intestinotrophic effects due to the presence of all three SCFA, just the butyrate portion or the total dose of SCFA? 3. How rapidly do SCFA augment intestinal adaptation and are the effects sustained?
Neonatal piglet IF preclinical model Similar in nutritional requirements, gastrointestinal physiology and metabolism Clinically relevant shortbowel syndrome and response to TPN Similar body composition to preterm infant Rapid growth and development
Experimental Design 48 hours old n = 120 Jugular Catheterization 80% Jejunoileal Resection TPN SCFA 9 mm Bu 60 mm Bu 4h 12h 24h 3d 7d Acute Chronic
Butyrate-supplemented PN increases ileal villous length 1000 Villus Length (µm) 800 600 400 200 0 Control SCFA 9Bu 60Bu Control < SCFA, P < 0.0001
A clinically feasible approach to butyrate delivery Butyrate supplemented PN not currently available SCFA are produced in vivo by bacterial fermentation of malabsorbed carbohydrates Short-chain fructooligosaccharies (scfos), a rapidly fermented prebiotic, may be a clinically efficacious means for delivering butyrate Synbiotic approach necessary? Pre- and probiotics SCFA: butyrate Intestinal adaptation
Experimental Design
Ileum mucosal weight is increased by the prebiotic treatment, regardless of time txt, p=0.005; day, p=<0.0001; txt x day, p=0.163
Prebiotic enhances ileal villous height Ileal villous height (µm) 600 P<0.001 b b ab a 400 200 0 Con Pre Pro Treatment Syn
Jejunal amino acid/peptide transport increased by prebiotics by Day 7 Δ µa/cm2 (10mM Glutamine) Δ µa/cm2 (10mM GlySar) 25 20 15 10 5 p<0.001 a b b b 7 6 5 4 3 2 1 b a b p=0.03 ab 0 Con Pre Pro Syn 0 Con Pre Pro Syn
Probiotic LGG ineffective at inducing adaptation No added benefit of synbiotic occasionally detrimental Impact on microbiota population potentially resulting in less butyrate production Further work is needed to select the optimal probiotic impact of SBS on infant microbiota Bifidobacteria predominate in healthy infants investigate butyrate producing bacteria for use as probiotics
Butyrate-suppl PN plasma [GLP-2] Plasma GLP-2 (pmol/l) 35 30 25 20 15 10 Control SCFA 9Bu 60Bu Control < SCFA Treatments, P = 0.007
Silencing taste receptors prevent butyrate from increasing GLP-2 Proglucagon mrna abundance (Proglucagon mrna/18s rrna) b a Control b b GPR43 sirna 0 mm Butyrate 7.5 mm Butyrate b b T2R38 sirna p < 0.05
What about humans with intestinal failure? Intact Gastrointestinal Tract Short-Bowel Syndrome
Role of GLP-2 in Intestinal Adaptation 1 Mucosal hyperplasia in GLP-2- treated murine small intestine 2 Control GLP-2 10 10 HIS ALA ASP GLY SER PHE PHE SER SERASP ASP GLU GLU MET MET ASN ASN THR THRILE ILELEU LEUASP ASP ASN ASN 30 20 LEU LEU ALA ALA ASP THR ILE LYS THR GLN GLNILE ILELEU LEUTRPTRP ASN ASNILE ILEPHE PHE ASP ASP ARG ARG ALA ALA 20 Peptide hormone produced in ileum and proximal colon 1 Induces local release of growth Treatments factors that enhance from enteroendocrine cells, subepithelial myofibroblasts, absorptive capacity and enteric of the neurons of the intestine 2 Drucker DJ, Erlich P, Asa SL, et al. Proc Natl Acad Sci U S intestine may improve A. 1996; 93:7911-7916. disease (1996) National Academy of Sciences, USA. management Evidence indicates GLP-2 plays a role in 1,2 intestinal adaptation 3-5 : levels after resection 3,4 crypt depth and villus height and stimulates intestinal blood 1. Hsieh et al. flow 2,3,4 Gastroenterol 2009;137(3):997-1005; 2. GATTEX (teduglutide [rdna origin]) for injection [package Native insert]. GLP-2 Bedminster, has anj: half-life NPS absorptive capacity 6 Pharmaceuticals; of only 7 minutes, 2012; 3. Drucker limiting et al. itspnas clinical USA. utility. 1996;93:7911-7 7916; 4. Jeppesen et al. Gut. 2000;47:370-376; 5. Vipperla et al. Exp Rev Gastroenterol Hepatol. 2011;5(6):665-678; 6. Jeppesen PB et al. Gastroenterol 2001;120:806-815; 7. Tee et al. Clin Exp Gastroenterol. 2011;4:189-196.
Teduglutide: A Recombinant GLP-2 AnalogWith Extended Half-life 1,2 1 10 HIS GLY ASP GLY SER PHE SER ASP GLU MET ASN THR ILE LEU ASP 30 20 ASP THR ILE LYS THR GLN ILE LEU TRP ASN ILE PHE ASP ARG ALA ASN LEU ALA Single amino acid substitution of alanine to glycine at the second position of the N-terminus Mean half-life of 1.3 hours in patients with SBS (vs 7 minutes for endogenous GLP-2) GATTEX is the first and only GLP-2 analog that increases villus height in the intestinal mucosa and enhances the absorptive capacity of the remaining bowel. 1. GATTEX (teduglutide [rdna origin]) for injection [package insert]. Bedminster, NJ: NPS Pharmaceuticals; 2012; 2. Tee CT, et al. Clin Exp Gastroenterol. 2011;4:189-196.
GLP-2 analog, teduglutide, increases jejunal villus height and crypt depth P = 0.024 Villus Height (µm) 900 600 300 P = 0.018 P = 0.030 Crypt Depth (µm) 0 50 100 150 200 250 P = 0.005 P = 0.029 P = 0.050 D0 D21 D42 D0 D21 D42 0 200 400 600 Crypt Depth (µm) Subjects with jejunostomy Subjects with colon-in-continuity
Design of multicenter prospective, randomized, double-blind, placebo-controlled study Placebo (n=43) Subjects 86 PNdependent subjects with intestinal failure Optimize PN Stabilize PN 0-8 wks 4-8 wks Teduglutide 0.05 mg/kg/d (n=43) Intestinal Biopsy 24 wks
Primary Endpoint 20 % Reduction in Weekly PS Volume from Baseline 100% Patients, % 80% 60% 40% 63% ** 30% 20% 0% Teduglutide Placebo (n = 43) Please see the Important Safety Information section in this presentation. * Definition of responder. Responder rate (%) was the primary endpoint in STEPS. ** P = 0.002 vs placebo. 1. GATTEX (teduglutide [rdna origin]) for injection [package insert]. Bedminster, NJ: NPS Pharmaceuticals; 2012; 2. Jeppesen PB, et al. Gastroenterology. 2012;143(6):1473-1481.
Teduglutide Reduced Mean Parenteral Support Volume 1,2 Weeks of Treatment Change in PN/IV Volume, L/week (SE) 0-0.5-1 -1.5-2 -2.5-3 -3.5-4 -4.5-5 -5.5-1.1 4 8 12 16 20 24-0.5-2.0* - 1.0 Teduglutide (n = 43) Placebo (n = 43) -3.0** -1.5-3.4*** -1.9-3.8*** -2.1-4.4*** -2.3 Adapted from Gastroenterology, 143(6), Jeppesen et al, Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure, 1473-81, 2012, with permission from Elsevier. Please see the Important Safety Information section in this presentation. * P 0.05, ** P 0.01, *** P 0.001. 1. GATTEX (teduglutide [rdna origin]) for injection [package insert]. Bedminster, NJ: NPS Pharmaceuticals; 2012; 2. Jeppesen PB, et al. Gastroenterology. 2012;143(6):1473-1481.
Representative change in small intestinal mucosa following 24 wks of 0.05 teduglutide administration. Baseline End-of-study
Teduglutide Reduced Day(s) on Parenteral Support 1,2 100% 80% 1 Day or More Off Parenteral Support per Week Patients, % 60% 40% 20% 54% 23% 0% (21/39) (9/39) Teduglutide Placebo Please see the Important Safety Information section in this presentation. 1. GATTEX (teduglutide [rdna origin]) for injection [package insert]. Bedminster, NJ: NPS Pharmaceuticals; 2012; 2. Jeppesen PB, et al. Gastroenterology. 2012;143(6):1473-1481.
Teduglutide Volume and Infusion Frequency PS reductions were sustained in the patients who completed 30 months of continuous treatment with Teduglutide 96% (21/22) of responders in STEPS who enrolled in STEPS2 sustained their response to GATTEX 93% (28/30) of patients achieved a 20% reduction of PS volume Patients who received placebo in STEPS and started Teduglutide in STEPS2 also achieved volume reductions after 24 months of treatment Total Exposure to Teduglutide Efficacy Endpoints Clinical Response ( 20% reduction of PS Volume) Mean reduction in PS volume from baseline (L/week) 30 months (n=30) 24 months* (n=29) 93% (28/30) 55.2% (16/29) 7.55 (65.6%) 3.11 (28.3% )
STEPS2 Results: Reduced Days on PS and Complete Weaning 1 The majority of patients who completed 30 months of Teduglutide treatment were able to reduce their days on PS, and a number of them were weaned off PS completely 60% (18/30) patients achieved 3 day reduction of PS per week 10 patients were weaned off PS completely Patients who received placebo in STEPS and started Teduglutide in STEPS2 also achieved reductions in days on PS, and some weaned off PS completely Total Exposure to Teduglutide Efficacy Endpoints Reduction of days per week on PS Weaned off PS completely 30 months (n=30) 24 months* (n=29) 1 d/wk - 70% 2 d/wk - 60% 3 d/wk - 60% 1 d/wk - 70% 2 d/wk - 60% 3 d/wk - 60% 10 2
Role of teduglutide and PEN in a neonatal piglet model of IF? Jugular catheterization 80% jejunoileal resection n = 72 TPN PEN (20%) Vehicle Teduglutide (0.1 mg/kg/d) TPN TPN + PEN PEN + 4h, 48h, 7d
Teduglutide and PEN small intestine villus height greater than either treatment alone. 800 600 400 200 0 Villus Length Duo Jej Ile PN PEN PN+Drug PEN+Drug TPN- PEN+ Representative mucosal architecture at 7d PEN+ villus length numerically greatest in all segments
Take Home Message Strategies to enhance intestinal adaptation, such as prebiotics and GLP-2 therapy, promise to reduce PN in individuals with intestinal failure.
Acknowledgements Anne L. Bartholome, Ph.D., R.D. NIDDK R01 DK 57682 David M. Albin, Ph.D. NPS Pharma Jennifer Woodard, Ph.D. Jen Barnes, BS Jens J. Holst, M.D., Ph.D.
Adverse Reactions* Teduglutide 0.05 mg/kg/day (n = 77) % of Patients Placebo (n = 59) % of Patients Abdominal pain 37.7 27.1 Upper respiratory tract infection 26.0 13.6 Nausea 24.7 20.3 Abdominal distension 19.5 1.7 Vomiting 11.7 10.2 Fluid overload 11.7 6.8 Flatulence 9.1 6.8 Hypersensitivity 7.8 5.1 Appetite disorders 6.5 3.4 Sleep disturbances 5.2 0.0 Cough 5.2 0.0 Skin hemorrhage 5.2 1.7 GI stoma complications** 41.9 13.6 * Adverse reactions in 5% of GATTEX -treated patients in placebo-controlled studies - STEPS and 004 ** Percentages based on 53 subjects with a stoma: Teduglutide (n = 31) and placebo (n = 22).